Dinesh Khanna

Objective: Existing patient‐reported outcome (PRO) measures for systemic sclerosis (SSc) have important limitations, including inadequate coverage of early disease and limited inclusion of diffuse cutaneous (dcSSc) and limited cutaneous (lcSSc) subtypes. This paper reports on the development of two PRO measures for early SSc in the Clinical Outcome Assessments for Systemic Sclerosis Clinical Trials (COAST) study, following regulatory guidance for clinical outcome assessments. Methods: Concept elicitation interviews were conducted with 42 individuals with dcSSc or lcSSc within 7 years of disease onset. Data were analyzed using a constant comparative approach. The concept prioritization scheme integrated symptom frequency, bother and health‐related quality of life ratings, subgroup analyses, and clinical expert input. Priority concepts were mapped to items from item libraries (PROMIS®, FACIT) and SSc‐specific measures, with new items developed during measure refinement. The item pool was reduced through expert consensus. Results: Across SSc subtypes, participants reported 52 symptoms and treatment side effects, spanning 16 domains. Raynaud's phenomenon was the most frequently reported symptom (81.0%), followed by swelling and pain (66.7% each); among the five most frequently reported symptoms, fatigue was rated most bothersome (mean=7.20, 0‐10 scale). Participants also reported 57 physical function impacts across 8 domains, and 16 socioemotional concerns across 4 domains. Two candidate measures were constructed: COAST Scleroderma Symptom Questionnaire (33 items) and COAST Scleroderma Function and Mood Questionnaire (20 items). Conclusions: The COAST measures address important gaps in SSc measurement, with content validity established through systematic patient input. The measures were designed for use in clinical trials to assess treatment benefit in early SSc.

Objective: Rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP), and novel autoantibodies including anti-malondialdehyde-acetaldehyde (MAA), anti-carbamylated protein (CarP), and anti-peptidylarginine deiminase (PAD) have been associated with clinical RA-associated interstitial lung disease (RA-ILD), but comprehensive autoantibody profiling across clinical and subclinical RA-ILD is lacking. Methods: We retrospectively identified patients with clinically-indicated chest computed tomography (CT) imaging (discovery dataset) and prospectively enrolled RA patients across 5 US sites for research chest CT screening (validation dataset). Clinical ILD (≥10% extent, symptomatic and diagnosed) and subclinical ILD (≥5% extent, undiagnosed with/without symptoms) were adjudicated by thoracic radiologists and analyzed by deep-learning quantitative computed tomography (QCT). Thirty-one biomarkers were measured and log-standardized. We used multivariable logistic regression with 10% false discovery rate (FDR) in the discovery dataset and considered replication if p<0.05 in the validation dataset. Results: We analyzed 1,005 participants: the discovery dataset comprised 149 clinical RA-ILD, 378 RA-noILD, 50 IPF, and 99 healthy controls; the validation dataset comprised 38 subclinical RA-ILD and 291 RA without subclinical ILD. Five autoantibodies replicated across both datasets for RA-ILD risk had higher QCT interstitial abnormalities: RF IgA, RF IgM, CCP3 IgA, CarP IgG, and PAD3 IgG. A composite panel of these autoantibodies had negative predictive values for RA-ILD of 0.81 (discovery) and 0.94 (validation). Conclusion: RF IgA/IgM, CCP3 IgA, CarP IgG, and PAD3 IgG were associated with clinical and subclinical RA-ILD. These biomarkers implicate carbamylation and citrullination in RA-ILD pathogenesis and may be clinically useful for risk stratification.

Objective: Systemic sclerosis (SSc) is characterized by immune dysregulation and fibrosis. We investigated whether abatacept modulates CD319/SLAMF7‐expressing cytotoxic T cells implicated in diffuse cutaneous SSc. Methods: In this ancillary ASSET trial analysis, peripheral blood mononuclear cells from 67 participants were analyzed at baseline and months one, three, and six. Flow cytometry quantified CD4+CD319+ and CD8+CD319+ T cells, cytotoxic and activation markers, and stimulated intracellular interleukin‐4 (IL‐4), IL‐17A, and interferon‐γ (IFN‐γ). Analyses compared abatacept‐treated molecular endotypes with placebo and related immune changes to modified Rodnan skin score (mRSS) change. Skin single‐cell RNA sequencing included five healthy controls and eight patients with SSc. Results: At baseline, CD319+ T cells showed greater cytokine production, activation, and granzyme and perforin expression than CD319− T cells in 60 evaluable participants ( P < 0.001 to P < 0.0001). Abatacept reduced CD4+CD319+ and CD8+CD319+ T cell frequencies at month six; placebo did not. Effects were strongest in patients in the fibroproliferative group, in whom CD8+CD319+ T cells decreased versus placebo (n = 7 versus n = 36; P = 0.0377). In this endotype, abatacept reduced IL‐4 in CD4+CD319+ and CD8+CD319+ T cells at month three ( P = 0.0468 and P = 0.0287) and IL‐17A in CD8+CD319+ T cells at month six ( P = 0.0004), whereas IFN‐γ was unchanged. Reduction in CD4+CD319+ T cells correlated with mRSS improvement in abatacept‐treated patients (r = 0.5297, P = 0.0423). Skin single‐cell RNA sequencing showed increased SLAMF7 expression in SSc T cells ( P = 0.017), enriched within cytotoxic subsets. Conclusion: CD319+ T cells represent highly differentiated, activated cytotoxic effector populations in SSc. Abatacept selectively modulates these cells and suppresses associated profibrotic and proinflammatory cytokines, particularly in the fibroproliferative subtype, in which CD319+ T cell reductions correlate with clinical improvement. image

SSc is the rheumatic disease with the highest individual mortality rate and is associated with substantial morbidity that severely affects quality of life. Organ fibrosis is a major contributor to irreversible damage in SSc, whereas early inflammatory manifestations largely reflect disease activity and may still respond to early immunomodulatory treatment. New imaging modalities, as well as novel applications of established techniques—such as lung US or improved US assessment of synovial involvement—offer promising opportunities to objectively distinguish activity i.e. early inflammation and early fibrosis from damage (i.e. late irreversible fixed vasculopathy or fibrosis) at the organ level. Differentiating these processes is essential for refining the therapeutic window of opportunity in this rare but devastating disease. This narrative review aims to provide an up-to-date overview of available and emerging imaging tools that may help discriminate activity from damage across organ systems involved in SSc, with a specific focus on early fibrotic and inflammatory manifestations.

Rationale: Immunosuppression is routinely used for non–idiopathic pulmonary fibrosis (IPF) interstitial lung diseases (ILDs), despite limited trial evidence and unclear impact on long-term outcomes. Objectives: To evaluate whether mycophenolate or azathioprine improves 3-year transplant-free survival and lung function trajectory in fibrotic ILD, including non-IPF idiopathic interstitial pneumonia (IIP), fibrotic hypersensitivity pneumonitis (fHP), and connective tissue disease (CTD)–associated ILD. Methods: We employed a clone-censor-weighting framework to emulate a randomized controlled trial in this multicenter retrospective study. Each patient was cloned and assigned to immunosuppression initiation within 6 months of enrollment or no initiation strategies and censored when the assigned strategy deviated from observed treatment. Stabilized inverse probability treatment and censoring weights were used. Measurements: The primary endpoint was 3-year transplant-free survival assessed with weighted Cox models across treatment strategies. Weighted generalized estimating equations were used to model lung function trajectory. Main results: Among 2270 included patients, 18% (186/1022) with non-IPF IIP, 30% (162/544) with fHP, and 31% (221/704) with CTD-ILD were initiated on immunosuppression within 6 months. Immunosuppression was not associated with improved survival within any ILD subtype but was associated with worse survival in non-IPF IIP (hazard ratio [HR] = 1.38; 95% CI, 1.04-1.84) and fHP (HR = 1.62; 95% CI, 1.09-2.40). Immunosuppression was not associated with differential lung function trajectory within any ILD subtype. Conclusions: In this study, immunosuppression initiation showed no evidence of benefit for 3-year transplant-free survival or lung function and was associated with higher mortality in select fibrotic ILD subtypes. Prospective randomized controlled trials are needed to inform patient care.

Introduction: Systemic sclerosis (SSc) is a rare, autoimmune, inflammatory and multisystem connective tissue disease, characterised by widespread vasculopathy and abnormal collagen deposition, leading to fibrosis of the skin and internal organs with significant morbidity and mortality. Preclinical and clinical evidence supports a pathogenic role for interleukin (IL)-31 signalling in driving fibrosis. Nemolizumab, a humanised monoclonal antibody targeting the IL-31 receptor alpha (IL-31RA) chain, is expected to confer both anti-inflammatory and antifibrotic effects by reducing skin thickening and slowing the progression of pulmonary fibrosis in SSc-associated interstitial lung disease. Methods: THESSALIA ( NCT07047690 ) is a phase II, randomised, double-blind, placebo-controlled, dose-ranging study with an extension phase evaluating the efficacy, safety and pharmacokinetics of nemolizumab in adult patients with limited or diffuse cutaneous SSc with active disease. 162 patients are planned to be recruited. Efficacy will be assessed at week 52 by change from baseline in modified Rodnan skin score (primary endpoint). Lung function and the overall disease activity will be assessed via change from baseline in forced vital capacity (FVC) in patients with SSc-associated interstitial lung disease and the revised Composite Response Index in SSc, respectively (key secondary endpoints). Comprehensive safety, pharmacokinetic, immunogenicity and exploratory biomarker assessments and genotyping are also included. Analysis: The THESSALIA study is currently recruiting patients and is planned to be conducted at approximately 120 sites globally. Ethics and dissemination: The sponsor has ensured that the local Institutional Review Board/Independent Ethics Committee in all countries involved approved the study. Trial registration number: NCT07047690 .

Objectives Despite earlier clustering studies on systemic sclerosis (SSc), how clinical subgroups differ in disease burden, treatment and patient–physician dynamics remains unclear. This study applied a novel clustering method to identify clinical subgroups. Design Data were analysed from 1906 adults with SSc and their treating rheumatologists across the USA, France, Germany, Italy, Spain, UK and Japan (March–September 2022). Setting Data were collected by Adelphi Real World as part of an independent survey titled the SSc I Disease Specific Programme, comprising data from the USA, France, Germany, Italy, Spain, UK and Japan. Participants Physicians completed case record forms; patients completed self-reported questionnaires. Latent class clustering was conducted using five physician-reported variables: affected body areas, symptoms, severity, flares in the past 12 months and remission status. Interventions This was a non-interventional, observational, retrospective study. Main outcome measures A cluster solution was selected based on model fit and clinical interpretability. We compared time to diagnosis, symptoms at diagnosis, postdiagnosis trajectories, physician management and patient treatment perspectives across clusters. Results We identified four clusters representing a gradient of disease severity, with all clusters comprising >75% females. Clusters 1/2 comprised younger patients with fewer concomitant conditions; Clusters 3/4 showed greater internal organ involvement and disease severity. Raynaud’s phenomenon (RP) was the most frequent first symptom (physician-reported: 73%–85%; patient-reported: 63%–79%), but those with first symptoms other than RP were diagnosed faster (mean 1.06 vs 1.62 years). Musculoskeletal involvement was most pronounced in Clusters 2/4. Postdiagnosis (3.7–7.2 years), the number of symptoms and affected body areas decreased in Cluster 1, increased in Cluster 4 and remained relatively stable in Clusters 2/3. Improvement in disease progression within the first 2 years postdiagnosis was more often reported in Clusters 1/2 vs 3/4 (33%–34% vs 8%–20%). Most patients across clusters reported that the main benefit they wanted from treatment was to get rid of the disease. Conclusions This analysis improves understanding of SSc beyond limited/diffuse subtypes. Musculoskeletal involvement emerged as a contributor to SSc burden, supporting its integration into monitoring/stratification strategies for earlier identification of high-risk patients.